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Curtius rearrangement

The (or Curtius reaction or Curtius degradation), first defined by Theodor Curtius rearrangement Curtius in 1885, is the thermal decomposition of an acyl to an with loss of Named after Theodor Curtius gas.[1][2] The isocyanate then undergoes attack by a variety of such as water, and , to yield a primary , or derivative respectively.[3] Several reviews have Reaction type Rearrangement been published.[4][5] reaction Identifiers Organic curtius- rearrangement Portal RSC ontology RXNO:0000054 ID

Contents Preparation of acyl azide Reaction mechanism Modifications Photochemical rearrangement Variations Darapsky degradation Harger reaction Synthetic applications Triquinacene Oseltamivir Dievodiamine See also References External links

Preparation of acyl azide

The acyl azide is usually made from the reaction of acid chlorides or anydrides[6] with or trimethylsilyl azide.[7] Acyl are also obtained from treating acylhydrazines with .[8] Alternatively, the acyl azide can be formed by the direct reaction of a with (DPPA).[9]

Diphenylphosphoryl azide Reaction mechanism

It was believed that the Curtius rearrangement was a two-step processes, with the loss of nitrogen gas forming an acyl , followed by migration of the R-group to give the isocyanate. However, recent research has indicated that the thermal decomposition is a concerted process, with both steps happening together, due to the absence of any nitrene insertion or addition byproducts observed or isolated in the reaction.[10] Thermodynamic calculations also support a concerted mechanism.[11]

Mechanism of the Curtius rearrangement

The migration occurs with full retention of configuration at the R-group. The migratory aptitude of the R-group is roughly tertiary > secondary ~ aryl > primary. The isocyanate formed can then be hydrolyzed to give a primary amine, or undergo nucleophilic attack with alcohols and amines to form and urea derivatives respectively.

Modifications

Research has shown that the Curtius rearrangement is catalyzed by both Brønsted[12] and Lewis acids, via the protonation of, or coordination to the acyl oxygen atom respectively. For example, Fahr and Neumann have shown that the use of boron trifluoride or catalyst reduces the decomposition temperature needed for rearrangement by about 100 °C, and increases the yield of the isocyanate significantly.[13]

Photochemical rearrangement

Mechanism of the photochemical Curtius rearrangement

Photochemical decomposition of the acyl azide is also possible.[14] However, photochemical rearrangement is not concerted and instead occurs by a nitrene intermediate, formed by the cleavage of the weak N–N bond and the loss of nitrogen gas. The highly reactive nitrene can undergo a variety of nitrene reactions, such as nitrene insertion and addition, giving unwanted side products.[15] In the example below, the nitrene intermediate inserts into one of the C–H bonds of the cyclohexane solvent to form N-cyclohexylbenzamide as a side product.

Variations

Darapsky degradation

In one variation called the Darapsky degradation,[16] or Darapsky synthesis, a Curtius rearrangement takes place as one of the steps in the conversion of an α-cyanoester to an . is used to convert the to an acylhydrazine, which is reacted with nitrous acid to give the acyl azide. Heating the azide in yields the ethyl carbamate via the Curtius rearrangement. Acid hydrolysis yields the amine from the carbamate and the carboxylic acid from the simultaneously, giving the product amino acid.[17] Harger reaction

The photochemical Curtius-like migration and rearrangement of a phosphinic azide forms a metaphosphonimidate[18] in what is also known as the Harger reaction (named after Dr Martin Harger from Leicester City).[19] This is followed by hydrolysis, in the example below with , to give a phosphonamidate.

Unlike the Curtius rearrangement, there is a choice of R-groups on the phosphinic azide which can migrate. Harger has found that the groups migrate preferentially to aryl groups, and this preference increases in the order methyl < primary < secondary < tertiary. This is probably due to steric and conformational factors, as the bulkier the R-group, the less favorable the conformation for phenyl migration.[20]

Synthetic applications

The Curtius rearrangement is tolerant of a large variety of functional groups, and has significant synthetic utility, as many different groups can be incorporated depending on the choice of used to attack the isocyanate.

For example, when carried out in the presence of tert-butanol, the reaction generates Boc-protected amines, useful intermediates in .[21][22] Likewise, when the Curtius reaction is performed in the presence of benzyl , Cbz-protected amines are formed.[23]

The Curtius rearrangement is used in the syntheses of the drugs tranylcypromine, candesartan, bromadol, terguride, , gabapentin, igmesine and tecadenoson.

Triquinacene

R. B. Woodward et al. used the Curtius rearrangement as one of the steps in the of the polyquinane triquinacene in 1964. Following hydrolysis of the ester in the intermediate (1), a Curtius rearrangement was effected to convert the carboxylic acid groups in (2) to the methyl carbamate groups (3) with 84% yield. Further steps then gave triquinacene (4).[24]

Oseltamivir

In their synthesis of the antiviral drug oseltamivir, also known as Tamiflu, Ishikawa et al. used the Curtius rearrangement in one of the key steps in converting the acyl azide to the group in the target molecule. In this case, the isocyanate formed by the rearrangement is attacked by a carboxylic acid to form the amide. Subsequent reactions could all be carried out in the same reaction vessel to give the final product with 57% overall yield. An important benefit of the Curtius reaction highlighted by the authors was that it could be carried out at room temperature, minimizing the hazard from heating. The scheme overall was highly efficient, requiring only three “one-pot” operations to produce this important and valuable drug used for the treatment of avian influenza.[25]

Dievodiamine Dievodiamine is a from the plant Evodia rutaecarpa, which is widely used in traditional Chinese medicine. Unsworth et al.’s -free total synthesis of dievodiamine utilizes the Curtius rearrangement in the first step of the synthesis, catalyzed by boron trifluoride. The activated isocyanate then quickly reacts with the ring in an electrophilic aromatic substitution reaction to give the amide in 94% yield, and subsequent steps give dievodamine.[26]

See also

Beckmann rearrangement Bergmann degradation Tiemann rearrangement Neber rearrangement

References

1. Curtius, Th. (1890). "Ueber Stickstoffwasserstoffsäure (Azoimid) N3H" (http://gallica.bnf.fr/ark:/12148/bpt6k90721q/f915.imag e.langEN) [On hydrazoic acid (azoimide) N3H]. Berichte der Deutschen Chemischen Gesellschaft zu Berlin. 23: 3023–3033. doi:10.1002/cber.189002302232 (https://doi.org/10.1002%2Fcber.189002302232). 2. Curtius, T. (1894). "20. Hydrazide und Azide organischer Säuren I. Abhandlung" (https://zenodo.org/record/1427976) [Hydrazides and azides of organic acids I. paper]. Journal für Praktische Chemie. 50: 275–294. doi:10.1002/prac.18940500125 (https://doi.org/10.1002%2Fprac.18940500125). 3. Kaiser, C.; Weinstock, J. (1988). "Amines from mixed carboxylic-carbonic anhydrides: 1-phenylcyclopentylamine" (http://www. orgsyn.org/demo.aspx?prep=cv6p0910). Organic Syntheses.; Collective Volume, 6, p. 910 4. Smith, P. A. S. (1946). "The Curtius reaction". Organic Reactions. 3: 337–449. 5. Scriven, Eric F. V.; Turnbull, Kenneth (1988). "Azides: their preparation and synthetic uses". Chemical Reviews. 88 (2): 297– 368. doi:10.1021/cr00084a001 (https://doi.org/10.1021%2Fcr00084a001). 6. Weinstock, J (1961). "Modified Curtius reaction". J. Org. Chem. 26: 3511. doi:10.1021/jo01067a604 (https://doi.org/10.1021% 2Fjo01067a604). 7. Warren, J. D.; Press, J. B. (1980). "Formation and Curtius rearrangement of acyl azides from unreactive acid chlorides". Synth. Commun. 10: 107–110. doi:10.1080/00397918008061812 (https://doi.org/10.1080%2F00397918008061812). 8. Pozsgay, V.; Jennings, H. J. (1987). "Azide synthesis with stable nitrosyl salts". Tetrahedron Lett. 28 (43): 5091–5092. doi:10.1016/s0040-4039(00)95598-9 (https://doi.org/10.1016%2Fs0040-4039%2800%2995598-9). 9. Shioiri, T.; Ninomiya, K.; Yamada, S. (1972). "New convenient reagent for a modified Curtius reaction and for peptide synthesis". J. Am. Chem. Soc. 94: 6203–6205. doi:10.1021/ja00772a052 (https://doi.org/10.1021%2Fja00772a052). 10. Rauk, A.; Alewood, P. F. (1977). "A theoretical study of the Curtius rearrangement. The electronic structures and interconversion of the CHNO species". Can. J. Chem. 55 (9): 1498–1510. doi:10.1139/v77-209 (https://doi.org/10.1139%2Fv7 7-209). 11. L'Abbe, G. (1969). "Decomposition and addition reactions of organic azides". Chem. Rev. 69 (3): 345–363. doi:10.1021/cr60259a004 (https://doi.org/10.1021%2Fcr60259a004). 12. Yukawa, Y.; Tsuno, Y. (1959). "The decomposition of substituted benzazides in acidic solvents, the acid ". J. Am. Chem. Soc. 81: 2007–2012. doi:10.1021/ja01517a055 (https://doi.org/10.1021%2Fja01517a055). 13. Fahr, E.; Neumann, L. (1965). "Curtius-Reaktion mit Bortrihalogeniden". Angew. Chem. 77 (13): 591. doi:10.1002/ange.19650771308 (https://doi.org/10.1002%2Fange.19650771308). 14. Wentrup, C.; Bornemann, H. (2005). "Curtius rearrangment of acyl azides revisited - formation of ". Eur. J. Org. Chem.: 4521–4524. doi:10.1002/ejoc.200500545 (https://doi.org/10.1002%2Fejoc.200500545). 15. Eibler, E.; Sauer, J. (1974). "Ein Betrag zur Isocyanatbildung bei der Photolyse von Acylaziden". Tetrahedron Lett. 15 (30): 2569–2572. doi:10.1016/s0040-4039(01)92295-6 (https://doi.org/10.1016%2Fs0040-4039%2801%2992295-6). 16. August Darapsky (1936) "Darstellung von α-Aminosäuren aus Alkyl-cyanessigsäuren" (Preparation of α-amino acids from alkyl cyanoacetic acids), Journal für Praktische Chemie, 146 : 250-267. 17. Gagnon, P. E.; Bovin, P. A.; Craig, H. M. (1951). "Synthesis of amino acids from substituted cyanoacetic ". Can. J. Chem. 29: 70–75. doi:10.1139/cjc-29-1-70 (https://doi.org/10.1139%2Fcjc-29-1-70). 18. Bertrand, G.; Majoral, J.; Baceiredo, A. (1980). "Photolytic rearrangement of phosphorus azide: evidence for a transient metaphosphonimidate". Tetrahedron Lett. 21 (52): 5015–5018. doi:10.1016/s0040-4039(00)71119-1 (https://doi.org/10.1016% 2Fs0040-4039%2800%2971119-1). 19. Harger, M. J. P.; Westlake, S. (1982). "Photolysis of some unsymmetrical phosphinic azides in methanol". Tetrahedron. 38 (20): 3073–3078. doi:10.1016/0040-4020(82)80195-6 (https://doi.org/10.1016%2F0040-4020%2882%2980195-6). 20. Harger, M. J. P.; Westlake, S. (1982). "Photolysis of some unsymmetrical phosphinic azides in methanol". Tetrahedron. 38 (20): 3073–3078. doi:10.1016/0040-4020(82)80195-6 (https://doi.org/10.1016%2F0040-4020%2882%2980195-6). 21. Am Ende, David J.; Devries, Keith M.; Clifford, Pamela J.; Brenek, Steven J. (1998). "A Calorimetric Investigation to Safely Scale-Up a Curtius Rearrangement of Acryloyl Azide". Organic Process Research & Development. 2 (6): 382–392. doi:10.1021/op970115w (https://doi.org/10.1021%2Fop970115w). 22. Lebel, H.; Leogane, O. (2005). "Boc-protected amines via a mild and efficient one-pot Curtius rearrangement". Organic Letters. 7 (19): 4107–4110. doi:10.1021/ol051428b (https://doi.org/10.1021%2Fol051428b). PMID 16146363 (https://pubmed. ncbi.nlm.nih.gov/16146363). 23. Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. (1988). "1-N-Acylamino-1,3-dienes from 2,4-pentadienoic acids by the Curtius rearrangement: benzyl trans-1,3-butadiene-1-carbamate" (http://www.orgsyn.org/demo.aspx?prep=cv6p0095). Organic Syntheses.; Collective Volume, 6, p. 95 24. Woodward, R. B.; Fukunaga, T.; Kelly, R. C. (1964). "Triquinacene". J. Am. Chem. Soc. 86 (15): 3162–3164. doi:10.1021/ja01069a046 (https://doi.org/10.1021%2Fja01069a046). 25. Ishikawa, H.; Suzuki, T.; Hayashi, Y. (2009). "High-yielding synthesis of the anti-influenza neuramidase inhibitor (-)-oseltamivir by three "one-pot" operations". Angew. Chem. Int. Ed. 48 (7): 1304–1307. doi:10.1002/anie.200804883 (https://doi.org/10.100 2%2Fanie.200804883). PMID 19123206 (https://pubmed.ncbi.nlm.nih.gov/19123206). 26. Unsworth, William P.; Kitsiou, Christiana; Taylor, Richard J. K. (5 July 2013). "An Expedient Protecting-Group-Free Total Synthesis of (±)-Dievodiamine". Organic Letters. 15 (13): 3302–3305. doi:10.1021/ol4013469 (https://doi.org/10.1021%2Fol4 013469). PMID 23786450 (https://pubmed.ncbi.nlm.nih.gov/23786450).

External links

"Mechanism In Motion: Curtius rearrangement" (https://www.youtube.com/watch?v=L9o2eFc0T9Q).

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This page was last edited on 3 August 2020, at 09:44 (UTC).

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